Inflammatory conditions are often associated with inappropriate regulation of cytokines, which are proteins that affect cellular functions. Han et al., Nature Cell Bial., E39-E40 (1999). Such inflammatory conditions include rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Protein-based agents which antagonize cytokines such as antibodies or soluble receptors have recently been approved for therapy in certain chronic inflammatory diseases. Since such biologic agents must be administered to patients by injection, alternative therapies wherein anti-inflammatory agents are orally administered may be more convenient and desirable.
Strategies that involve modulating the activity of kinases involved in inflammatory regulatory pathways using small molecule inhibitors may provide alternative therapeutic approaches to treat inflammation. Kinases play a major role in the upregulation of major pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α). One such kinase is mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP K2 or MK2) which mediates multiple p38 MAPK-dependent cellular responses. MK2 is phosphorylated by p38 MAP kinase in response to certain environmental stress or inflammatory cytokines. Kotlyarov et al., Nat. Cell Biol., 1: 94-97 (1999). Upon stimulation,. MK2 phosphorylates heat shock protein (HSP) 27, tyrosine hydroxylase, and leukocyte-specific protein-1 (LSPI), Duraisarny et al., Expert Opin. Ther. Targets, 12: 921-936 (2008).
Experimental observations support the prediction that inhibition of MK2 is an appropriate approach for treating inflammation. Kotlyarov et al. in Nat. Cell Biol., 1: 94-97 (1999) showed that mice that lack MK2 function, due to a mutation in the mouse MK2 gene, show increased stress resistance and survive LPS-induced endotoxic shock. These obervations were explained by a reduced production of the pro-inflammatory cytokine TNF-α. Id. In addition, in an animal model of rheumatoid arthritis, deletion of the MK2 gene in mice conferred protection to the mice toward collagen-induced arthritis. Heger) et al., J. Immunol., 177: 1913-1917 (2006).
Thus, due to MK2's involvement in inflammatory responses, it serves as a promising target for therapeutic intervention. Small molecule therapeutic agents that inhibit the activity of MK2 would be particularly useful for treating inflammatory conditions in humans and animals.